Genetic resistance to prion disease including vCJD

11 June 2015

Researchers have reported important evidence of a genetic mutation that protects against prion diseases.

Prion diseases are a group of rare progressive (and ultimately lethal) neurodegenerative disorders that are caused by abnormally shaped prion protein. Normal prion protein (PrP) is thought to be involved in a number of key neurological processes; abnormal, misfolded forms of the protein can effectively propagate themselves by binding to normal prions and converting them to abnormal forms. Clumps of misfolded prion protein accumulate in the brain, destroying neurons and creating characteristic holes or vacuoles in the brain.

In familial forms of the disease (such as familial Creutzfeldt-Jakob disease), individuals inherit mutations in the PRNP gene. Acquired forms of disease such as variant Creutzfeldt-Jakob disease (vCJD) or kuru result from external exposure to abnormal prion proteins. Kuru is a condition associated with the Fore communities in Papua New Guinea, who traditionally consumed contaminated human flesh as part of funeral rituals. Variant CJD is caused by consumption of meat from cows with bovine spongiform encephalopathy (BSE). Finally, sporadic cases of disease arise in individuals with no known exposures to abnormal prions and no PRNP gene mutations.

Researchers report in the journal Nature on a PRNP gene variant (G127V) associated with resistance to Kuru in the Papua New Guinea Fore populations. They created transgenic mice expressing either a common human PRNP gene variant (M129V) already linked with resistance to prion diseases or the new PRNP gene variant (G127V). Mice expressing either variant were found to be completely resistant to both kuru and classical Creutzfeldt–Jakob disease (CJD) prions, but could be infected with variant Creutzfeldt–Jakob disease (vCJD) prions. However, mice expressing only PRNP gene variant V127 were completely resistant to all prion strains. The PrP V127 protein also acted as an inhibitor of normal prion propagation.

The researchers conclude that understanding why the human PrP V127 protein is unable to propagate different sorts of disease-linked prions could ‘provide key insights into prion propagation’ and lead to the creation of interventions to prevent CJD and other neurodegenerative disorders from developing. Lead researcher Prof John Collinge of the MRC Prion Unit at UCL commented: "This could provide great insights into how the disease works and ultimately how to stop it".

There is also hope that insights into protein propagation and aggregation could prove valuable for other more common forms of neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases, that also involve the harmful accumulation of abnormal forms of one or more proteins in the brain.

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